Blood Pressure, Artery Size, and Artery Compliance Parallel Bone Size and Strength in Mice With Differing Ece1 Expression

Abstract

The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.

Endothelin signaling regulates mineralization and posttranscriptionally regulates SOST in TMOb cells via miR 126-3p

“…Previous work in our laboratory using the recombinant congenic mice HcB-8 and HcB-23 identified ECE-1, the gene encoding ECE-1, as a positional candidate for a pleiotropic quantitative trait locus influencing bone strength and size in skeletally mature mice (Saless et al 2009(Saless et al , 2010(Saless et al , 2011aKristianto et al 2016). In these mice, higher expression of ECE-1 is associated with the presence of larger, stronger, and denser bones (Wang et al 2013). We hypothesized that big ET-1 signaling promotes osteoblast differentiation and mineralization in normal physiology.…”

“…In these mice, higher expression of ECE‐1 is associated with the presence of larger, stronger, and denser bones (Wang et al. ). We hypothesized that big ET‐1 signaling promotes osteoblast differentiation and mineralization in normal physiology.…”

Endothelin Signaling in Bone

“…Endothelial cells are the primary source of ET1 and have a high density of EDNRB, so autocrine signaling favors vasodilation and hypotensive responses, while paracrine signaling leads to hypertensive responses. In experiments we performed using the same mice in which we identified Ece1 as a candidate gene for bone biomechanical performance, we found that mice harboring a high-expressing Ece1 allele had larger femoral and arterial cross-sections, greater arterial compliance, and lower BP than mice harboring a low-expressing Ece1 allele 52 .…”

Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function

“…The LCCA was stretched 150% axially to mimic in vivo length (Tian et al, 2013; Wang et al, 2013a), pressurized to 90 mmHg, and allowed to equilibrate at 37°C for 30 minutes. Sinusoidal pressure cycles of 90-120 mmHg at 1 Hz were applied for pre-conditioning to achieve a consistent mechanical response (Fung et al, 1979).…”